The objectives of the proposed work are a better understanding of the regulation of cholesterol biosynthesis, the properties of the enzymes involved, and the design of specific inhibitors of enzymes acting between mevalonate and squalene. The reason for the latter endeavor is the discovery in this laboratory that intermediates of cholesterol biosynthesis derived from mevalonate, and probably preceeding the synthesis of squalene, are diverted even under physiological conditions to a metabolic pathway not leading to sterols. We should like to enhance this "shunt" pathway. A further endeavor of the investigations is to examine the effects of chronic administration of mevalonate on plasma lipoproteins as it was found in this laboratory that (a) administration of mevalonate to animals supresses HMG-CoA reductase to very low levels (the enzyme that generates endogenous mevalonate); (b) that beer and wine are rich in mevalonate and (c) that according to Yano et al. (New England J. Med. 297:405, 1977) "heavy" beer drinking protects against coronary heart disease. We need to have an answer to the question: Is the protection efforded by beer drinking the result of chronic consumption of mevalonate?